NKTR-255 Vs Placebo to Enhance Complete Responses and Durability Following CD19-Directed CAR-T Therapy in Patients with Relapsed/ Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background:Autologous T cells engineered to express CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory large B-cell lymphoma (LBCL). However, more than half of patients fail to achieve remission or will eventually relapse. Thus, strategies to improve long-term efficacy of CAR-T cell products are needed. NKTR-255 is an investigational polymer-conjugated IL-15 agonist, that activates, proliferates and expands natural killer and CD8+ T-cells in vivo, as well as promote the survival and expansion of memory CD8+ T cells. Preclinical data in B-cell lymphoma xenograft models have shown that NKTR-255 enhanced proliferation, survival, and anti-tumor activity of human CD19 CAR-T cells (Hirayama, 2023). Further, clinical studies have shown that NKTR-255 expanded CAR-T and CD8+ T cells in patients with R/R NHL who previously received CAR-T therapy (NCT04136756), and enhanced CAR-T cell trafficking to the tumor microenvironment (Muffly, 2024; NCT03233854). Here, we describe results of the Phase 2 dose exploration trial evaluating NKTR-255 to enhance complete responses and durability of CD19 CAR-T therapy (NCT05664217). Methods: This is a phase 2 randomized, double-blind, placebo-controlled, multicenter study of NKTR-255 vs placebo following CD19 CAR-T therapy. Eligible patients with R/R LBCL were treated with one of two FDA-approved CAR-T products (axicabtagene ciloleucel or lisocabtagene maraleucel). Patients received study drug intravenously starting +14 days following CAR-T infusion, with continued dosing every 21 days for up to 5 months. The primary endpoint was complete response rate (CRR) by blinded independent central review (BICR) at month 6 after CD19 CAR-T cells with NKTR-255 compared with placebo. Efficacy was assessed by PET-CT reported according to Lugano Response Criteria 2014. Key secondary and exploratory objectives included safety/tolerability, NKTR-255 PK and CAR-T PD. CAR-T cells were quantified by flow and ddPCR. Treatment related adverse events (TRAEs) were reported from the start of NKTR-255 treatment. Results: A total of 15 patients with LBCL were randomized between Mar and Dec 2023. All patients received CD19 CAR-T cell therapy and ≥1 dose of study treatment; 12/15 (80%) received axi-cel and 3/15 (20%) received liso-cel preceding NKTR-255 or placebo. In total, 11 were randomized to the NKTR-255 group (5 at 1.5 µg/kg; 3 at 3.0 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 were randomized to placebo. LDH and histology was similar between the NKTR-255 and placebo groups, with the exception of tumor burden (NKTR-255 group median 1408 vs 940 mm2 for placebo). Treatment with NKTR-255 following CAR-T was well-tolerated. Among the 11 who received NKTR-255, infusion-related reaction (IRR) and fever was reported in 2/11 (18%) and 3/11 (27%) pts, respectively; these occurred ~6-8 hrs after infusion, all were grade 1/2 and resolved within 24 hrs with supportive care alone. No IRR or fever was reported with placebo. The most common grade ≥3 TRAEs reported with NKTR-255 in >1 patient was neutrophil count decrease 5/11 (46%), platelet count decrease 2/11 (18%), and lymphocyte count decrease 2/11 (18%); all resolved with no clinical sequelae. One patient had a grade 5 event of Guillain-Barré-syndrome on axi-cel with symptoms beginning prior to NKTR-255 and was deemed not related to study treatment by an independent DMC. Per intent-to-treat and BICR efficacy, the CRR at month 6 for the NKTR-255 group was 8/11 (73%) vs 2/4 (50%) with placebo. Per investigator, the conversions rate from SD/PR to CR at month 6 for the NKTR-255 group was 2/8 (25%) vs 0/2 (0%) with placebo. Per response-evaluable population by Investigator assessment, CRR at month 6 for the NKTR-255 group was 8/10 (80%) vs 2/4 (50%) with placebo. Notable re-expansion of CD8+ CAR-T cells occurred in 8/11 (73%) for NKTR-255 group vs 0/4 (0%) with placebo. NKTR-255 PK results were consistent with prior reported data. Additional longitudinal correlative analyses will be presented at the meeting. Conclusions: Preliminary data from the randomized, double-blind, placebo-controlled study showed NKTR-255 adjuvant to CD19 CAR-T cell therapy in LBCL was well-tolerated, safe and efficacious to enhance the CR rate of CD19 CAR-T cell therapy alone at month 6. Additional confirmatory studies with NKTR-255 as adjuvant treatment to CAR-T therapy and other cellular therapies are warranted.